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Acquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib

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dc.contributor.authorKim, Seulki-
dc.contributor.authorKim, Tae Min-
dc.contributor.authorKim, Dong-Wan-
dc.contributor.authorKim, Soyeon-
dc.contributor.authorKim, Miso-
dc.contributor.authorAlm, Yong-Oon-
dc.contributor.authorKeam, Bhumsuk-
dc.contributor.authorHeo, Dae Seog-
dc.date.accessioned2020-04-27T11:00:50Z-
dc.date.available2020-04-27T11:00:50Z-
dc.date.issued2019-07-
dc.identifier.citationCancer Research and Treatment, Vol.51 No.3, pp.951-962-
dc.identifier.issn1598-2998-
dc.identifier.other81441-
dc.identifier.urihttps://hdl.handle.net/10371/165223-
dc.description.abstractPurpose Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1. Materials and Methods We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3' mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines. Results We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit alpha (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase alpha (PI3K alpha) inhibitor. Conclusion Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3K alpha inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.-
dc.subjectMET tyrosine kinase inhibitor-
dc.subjectCapmatinib-
dc.subjectMET amplification-
dc.subjectNon-small cell lung carcinoma-
dc.subjectAcquired resistance-
dc.titleAcquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib-
dc.typeArticle-
dc.contributor.AlternativeAuthor김동완-
dc.contributor.AlternativeAuthor허대석-
dc.identifier.doi10.4143/crt.2018.052-
dc.citation.journaltitleCancer Research and Treatment-
dc.identifier.scopusid2-s2.0-85065306468-
dc.citation.endpage962-
dc.citation.number3-
dc.citation.startpage951-
dc.citation.volume51-
dc.identifier.urlhttps://www.e-crt.org/journal/view.php?doi=10.4143/crt.2018.052-
dc.identifier.rimsid81441-
dc.identifier.sci000476707300011-
dc.identifier.kciidART002486336-
dc.description.isOpenAccessY-
dc.contributor.affiliatedAuthorKim, Dong-Wan-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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